Menu

Filter articles published since 2015 by topic, disease, or article type.

Guidlines for filtering

Results are filtered to show all matching articles from a particular category, and to show only articles that match all selected categories.

For instance, if "Biomarkers" and "Genetics" are selected in the Topic category, and "Multiple sclerosis" is selected in the Disease category, all results that match EITHER the Biomarkers OR Genetics Topic category will be shown, but only if they also match the Multiple sclerosis Disease category; i.e. Boolean search of [("Biomarkers" OR "Genetics") AND "multiple sclerosis"]

Filter articles published since 2015 by topic, disease, or article type.

Guidlines for filtering

Results are filtered to show all matching articles from a particular category, and to show only articles that match all selected categories.

For instance, if "Biomarkers" and "Genetics" are selected in the Topic category, and "Multiple sclerosis" is selected in the Disease category, all results that match EITHER the Biomarkers OR Genetics Topic category will be shown, but only if they also match the Multiple sclerosis Disease category; i.e. Boolean search of [("Biomarkers" OR "Genetics") AND "multiple sclerosis"]

Pee P75: A Potential Biomarker of ALS Progression?

In the February 22 Neurology online, scientists reported that a fragment of the p75 neurotrophin receptor could mark progression for amyotrophic lateral sclerosis (ALS). Researchers led by Mary-Louise Rogers, Flinders University Centre of Neuroscience in Adelaide, Australia, and Michael Benatar, University of Miami, Florida, confirmed that ALS patients shed more of the extracellular domain of this receptor into their urine than healthy controls do, and that their p75ECD levels rise as disease worsens. The researchers propose that p75ECD could become the first marker of ALS progression, and that it could prove useful in clinical trials.

“The difference between the controls and ALS patients is dramatic, and the increase over time seems compelling,” said Mark Bothwell, University of Washington, Seattle, who was not involved in the study.

No fluid-based biomarker has emerged to reliably track ALS. Blood levels of light and heavy chains of neurofilament distinguish ALS patients from controls, but they do not change as disease progresses (see Jun 2015 news; Boylan et al., 2009).

P75 receptor is highly expressed during development, downregulated, then re-emerges in injured or diseased neurons. Signaling through this receptor contributes to both survival and apoptotic processes. In patients with ALS, the receptor appears on the surface of apoptotic motor neurons and Schwann cells. It also appears on hippocampal neurons in people with Alzheimer’s disease (Seeburger et al., 1993; Kerkhoff et al., 1991; Ito et al., 2016). As part of the protein’s normal processing, the extracellular domain sheds from the cell surface and winds up in the urine (Smith et al., 2015). Previously, Rogers and others reported that p75ECD levels are higher in patients’ urine than in controls (Shepheard et al., 2014).

In SOD1 G93A ALS models, urine p75ECD climbs as the mice deteriorate, but it was unknown if that happens in ALS patients, too (Matusica et al., 2016). To find out, first author Stephanie Shepheard at Flinders analyzed samples from the South Australian Motor Neuron Disease Clinic in Adelaide, and from the Kessenich Family ALS Center at the University of Miami. She used ELISA to measure p75 in the urine of 54 ALS patients who averaged 64 years of age, as well as 45 of their healthy spouses and friends, average age 50. The researchers normalized urine p75ECD measurements to the levels of creatinine, a byproduct of muscle metabolism, in order to account for people’s hydration level.

ALS patients had an average 5.6 ng of urinary p75ECD per mg creatinine, compared to 3.6 in controls (see image below). The assay yielded the same measurements for patients regardless of what time of day the samples were taken, whether the samples underwent freeze-thaw cycles, or were stored at varying temperatures. This suggests the assay is robust, wrote the authors.

Of the 54 ALS patients, 31 gave up to five additional urine samples, each taken a few months apart. As their disease worsened, p75ECD levels went up by about 0.19 ng/mg creatinine per month. Spaghetti plots showed that levels rose steadily in almost every patient tested during a period of 30 to 50 months. By comparison, cross-sectional data from the controls suggested an age-related p75ECDincrease of 0.32 ng/mg creatinine per decade.

The increase in ALS patient p75ECD correlated with a worsening on the ALS Functional Rating Scale of about 0.82 points per month. Higher p75ECD levels at diagnosis also predicted shorter survival.

Results suggest that p75ECD could join a few other potential ALS biomarkers and be the first to track with disease progression, claim the authors. However, given that urine levels of p75ECD overlap with those of controls, it is unlikely to work as a diagnostic marker, Benatar said. Since p75ECD is a general marker of neurodegeneration, it will not be specific for ALS, either.

Being able to assay urine instead of blood offers a distinct advantage, however, he said. Interestingly, p75ECD has been proposed to protect against Aβ toxicity and has been found at low levels in the CSF and high levels in serum of AD patients (Yao et al., 2015; Jiao et al., 2015).

“It is exciting that there may be a credible biomarker for ALS with the potential for monitoring disease progression and effectiveness of treatments,” said Elizabeth Coulson, University of Queensland, Australia, who was not involved in this study but has collaborated with this group on a previous p75 paper. She added that since other groups have associated p75ECD with Alzheimer’s disease, researchers could look at this biomarker in a range of diseases.

If the concentration of this protein fragment changes dynamically in response to treatments that slow neurodegeneration, that might make a potential pharmacodynamic indicator, said Benatar. He acknowledged that the healthy controls in this study were significantly younger than the patients, and the current analysis only cross-sectional. However, since p75ECD appears to change only slowly in healthy controls, he expects it will barely change over a period of 18 months, the timeframe of most ALS trials.

Benatar and Rogers are working with the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) consortium to reproduce this data in a larger cohort. The consortium’s Phenotype-Genotype-Biomarker study collects urine, blood, and CSF samples from ALS patients every three to six months while clinically assessing cognitive and behavioral symptoms. With 700 patients examined longitudinally, the study will be able to determine whether p75ECD can predict future rates of functional decline, Benatar said.

Bothwell added that p75ECD might be a useful antecedent marker in people with suspected familial ALS. “With ALS, about half of the motor neurons can be lost before a major functional deficit is detected,” he said. He also noted it would be interesting to determine whether p75ECD comes from Schwann cells or motor neurons, and whether it reflects higher expression or faster cleavage of p75.

Post navigation

Filter articles published since 2015 by topic, disease, or article type.

Guidlines for filtering

Results are filtered to show all matching articles from a particular category, and to show only articles that match all selected categories.

For instance, if "Biomarkers" and "Genetics" are selected in the Topic category, and "Multiple sclerosis" is selected in the Disease category, all results that match EITHER the Biomarkers OR Genetics Topic category will be shown, but only if they also match the Multiple sclerosis Disease category; i.e. Boolean search of [("Biomarkers" OR "Genetics") AND "multiple sclerosis"]